Grantee Research Project Results
2011 Progress Report: Berkeley/Stanford Children’s Environmental Health Center
EPA Grant Number: R834596Center: UC Berkeley/Stanford Children’s Environment Health Center
Center Director: Tager, Ira
Title: Berkeley/Stanford Children’s Environmental Health Center
Investigators: Hammond, S. Katharine , Tager, Ira , Shaw, Gary M. , Balmes, John R. , Lurmann, Fred , Hubbard, Alan , Eisen, Ellen , Nadeau, Kari , Mann, Jennifer , Padula, Amy , Gale, Sara L , Noth, Elizabeth
Current Investigators: Hammond, S. Katharine , Tager, Ira , Gale, Sara L , Shaw, Gary M. , Balmes, John R. , Padula, Amy , Eisen, Ellen , Mann, Jennifer , Nadeau, Kari
Institution: University of California - Berkeley , Harvard University , Stanford University , University of California - San Francisco , Sonoma Technology, Inc.
Current Institution: University of California - Berkeley , Stanford University
EPA Project Officer: Callan, Richard
Project Period: May 7, 2010 through May 6, 2013 (Extended to May 6, 2014)
Project Period Covered by this Report: May 7, 2011 through May 6,2012
Project Amount: $1,091,783
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
Project 1: Effect of Multi-Level Environmental Exposure on Birth Outcomes
To determine if the associations between adverse pregnancy outcomes (low birth weight, pre-term and small for gestation age) and exposure to ambient air pollutants and endotoxin are increased in women who reside in impoverished neighborhoods and are socially disadvantaged at the individual level. Elevated air pollution levels and higher traffic density have been implicated as having adverse effects on the health of children and adults. Outcomes include reduced birth weight and gestational duration, decreased pulmonary function and coronary heart disease. Many of the outcomes are more common within communities with lower socioeconomic status (SES) and more ethnic diversity; these are the same communities that tend to have higher air pollution and traffic-density, at least in the United States. It may be a case of environmental justice with important health consequences and may invoke policy change to address such potential injustice.
Project 2: Exposure to Air Pollutants and Risk of Birth Defects
Birth defects are the leading cause of infant mortality in the United States. Our Center's research efforts will enhance scientific understanding of the potential environmental etiologies of birth defects, which will undoubtedly have important implications for risk assessment and prevention of these common, costly, and often deadly outcomes of pregnancy. Specifically, in this project we are conducting a rigorous population-based epidemiologic study to determine whether exposures to specific air pollutants and mixtures of air pollutants, during critical periods of fetal organogenesis, are associated with women delivering infants/fetuses with structural birth defects.
Project 3: Ambient Pollutants/Bioaerosol Effects on Treg Function
The overall goal of this research is to further understand the link between indicators of exposure and outcomes on human health by studying immune system changes in subjects exposed to elevated levels of ambient air pollution. We hypothesize that immunological indicators linked to environmental exposure and health outcomes will elucidate the role and mechanism of air pollution in asthma, a link that is theoretically understood, circumstantially clear, but not yet proven. We have developed a comprehensive novel indicator of hazard exposure that can be performed on one drop of blood. We will correlate cellular, serological, and epigenetic biomarker changes in peripheral blood, which can be broadly applied to an individual health outcome. The objectives of the research are to: (1) examine the link between specific immune indicators and ambient air pollution exposure (level of exposure, chronicity of exposure, and type of exposure: ozone, NO/NO2, CO, PM2.5, PM10, sulfate, elemental carbon, polyaromatic hydrocarbons, daily naphthalene, endotoxin, fungal spores, and/or pollens) through a database collected in a large population in Fresno, CA; and (2) characterize the relationship between immune indicators and health outcomes of asthma.
Community Outreach and Translation Core
To engage community-based stakeholders in the ongoing conduct of studies of the effects of air pollution in children in the San Joaquin Valley by Center investigators and to facilitate translation of results of these studies into useful information for such stakeholders.
Exposure Core (ExC)
The purpose of the Exposure Core was to supply exposure data for the three projects. This requires acquisition and processing of routinely measured ambient air pollutants, and collection of new PAH and endotoxin data in the San Joaquin Valley (SJV), as well as the development of models for exposure assessment.
Progress Summary:
Project 1: Effect of Multi-Level Environmental Exposure on Birth Outcomes
Building on the pilot analysis of item response theory (IRT) for the FACES cohort, we applied it to the SAGE cohort in Fresno County, which includes births between 2000-2006 (N = 90,196). These neighborhoods include the GIS data that were collected previously (road network and traffic, alcohol and cigarette sales, wildfires, Superfund sites, grocery stores and farmers markets, schools and daycares, hospitals, water quality, and crime). In IRT, several variables are used to make a scale that describes a latent variable. The latent variable often is unobserved or not quantified by one measure. In our analysis, neighborhood deprivation is the latent variable, because we do not have one variable that captures the complexity of deprivation—there are several. There also are many different IRT modeling methods, but, in general, the best model is defined by the mean-squared error of prediction. The item parameters are all of the covariates, which we converted to be positive and negative (0 = negative neighborhood influence, 1 = positive neighborhood influence). For example, if there was an alcohol outlet in a study subject's neighborhood, his or her response would be 0 for that item. If there was a park in that neighborhood, the response would be 1. Scoring is based on the proportion of positive neighborhood characteristics. Item parameters are fixed, and we maximize the likelihood for our deprivation score.
We also continued analyses of the associations between the individual air pollutants on pre-term birth comparing the highest quartile versus the lowest three quartiles. This was building on the preliminary analyses of traffic density.
Project 2: Exposure to Air Pollutants and Risk of Birth Defects
In this project, we are using data from the largest case-control study conducted to date in the United States on birth defects—the National Birth Defects Prevention Study. We limit our inquiries to the California study site, which is being conducted in the San Joaquin Valley—an area with demonstrated poor air quality. This study includes information on 30 birth defect phenotypes. Our initial analyses have targeted three specific birth defect phenotypes that, based on past investigations, appear to be more environmentally-sensitive in their etiologies, namely neural tube defects, oral clefts, and the abdominal wall defect known as gastroschisis. Eligible cases included live births, stillbirths, and pregnancy terminations and were selected from the centers surveillance system based on strict eligibility criteria. Controls included non-malformed live-born infants randomly selected from birth hospitals to represent the population from which the cases arise.
Initial analyses have included 802 cases (215 neural tube defects, 293 cleft lip with or without cleft palate, 129 cleft palate only; 169 gastroschisis) and 849 controls. Interviews were conducted with mothers of 71% of eligible cases and 69% of controls. Mothers reported a full residential history from one month before conception through delivery, including start and stop dates for each residence. Addresses were geocoded using the Centrus Software, which combines reference street networks from Tele Atlas and United States Postal Service data. Geocodes were available for 95% of cases and 93% of controls.
Ambient air pollution measurements and traffic metrics were assigned to each of the geocoded residences reported by the study subjects during the first and second month of pregnancy. Exposure assignments were made if the geocodes were within the San Joaquin Valley and accounted for at least 75% of the first and second month of pregnancy. The pollutants included: ozone (O3), nitrogen dioxide (NO2), nitrogen oxide (NO), carbon monoxide (CO), particulate matter less than 10 μg/m3 (PM10), and PM less than 2.5 μg/m3 (PM2.5). Daily 24-hour averages for all of the pollutants as well as a daily daytime 8-hour maximum for ozone then were averaged over the first two months of pregnancy.
Our analyses find evidence that higher exposure to traffic-related ambient air pollutants CO, NO and NO2 and lower exposure to O3 during the first two months of pregnancy appear to be associated with increased odds of neural tube defects in the San Joaquin Valley of California. In contrast, higher ozone was associated with an increased odds of gastroschisis and higher CO was associated with decreased odds of cleft lip with/without cleft palate. We found no associations between particulate matter and the selected birth defects. We have initiated detailed analyses on the largest grouping of birth defects— congenital heart defects.
Project 3: Ambient Pollutants/Bioaerosol Effects on Treg Function
The work on the project aims has proceeded smoothly and at the pace anticipated. All has progressed according to timelines and all subjects have been recruited and are enrolled in the study. We are in the process of performing all cellular and molecular analyses on the blood samples obtained from the subjects. Some preliminary results and publications have occurred and these are detailed below. The aims of the project are unchanged.
As described in the preliminary results section below, significant immunotoxic effects were observed using in vivo and ex vivo studies.
Overall Impact: The proposal is aimed to innovatively examine whether chronic ambient air exposures, the health outcomes of individual children, and changes in the immune system are correlated. The results are essential for understanding immune mechanisms that could be related to exposure and health outcomes. Overall, the results would help in decreasing and preventing the burden of asthma and allergy and reducing exposure to air pollution.
Results expected during the project (output). Our preliminary data demonstrate that:
- DNA methylation of the FoxP3 gene results in decreased FoxP3 protein levels in Treg and that the levels of FoxP3 decrease are associated with increases in levels of exposure to polycyclic aromatic hydrocarbons.
- Downregulation of chemokine receptor/cognate ligand pairs (CCR8/CCL1) is worsened by exposure to polycyclic aromatic hydrocarbons.
- Decreases in Treg-associated (TGF-β and IL-10) and increases in Th2-associated plasma markers (IL-4 and IL-13) correlate with increased levels of exposure to ambient air pollution.
- Higher degrees of Treg impairment correlate with severity of asthma, and
- Lower levels of Treg immune indicators can be detected in non-asthmatic children exposed to elevated levels of ambient air pollution and that if the Treg immune indicators increase over the four time points of the study (baseline, 6 mo, 12 mo and 18 mo), then these children might be at risk for developing asthma. Definitive analysis for the positive predictive value of a Treg immune indicator is outside the scope of this study but we plan to collect evidence in this proposed research to further test predictive value in the future.
We expect our results to:
- Provide sufficient evidence to help understand the link between the environmental hazard, exposure (individual estimate exposures), and the health outcomes (asthma) through the database collected in a large population in Fresno, CA.
- Characterize the relationship between ambient air pollution exposure and biomarkers that can be used to indicate the health outcomes of asthma.
Preliminary Results:
CD45RO+Treg are decreased in FA subjects Based on experiments in which we calculated the absolute numbers of live Treg and effector CD4+ T cell for each subject sample, we found that the CD45RO+ (adaptive or short-lived) Treg from FA subjects were lower in absolute numbers (Figure 1A) compared to FNA. CD45RO+ (memory) conventional T cells were increased in the FA population (Figure 1B), indicating the possible conversion of CD45RO+Treg into CD45RO+ conventional CD4+ T cells in vivo. Our laboratory has confirmed that these are memory Treg via other memory cell markers (i.e., CD62Llo, CD44hi, HLA-DRhi; data not shown). These preliminary results show the feasibility of identifying different subsets within the Treg population by the high resolution immunophenotyping methods performed in my laboratory. The results suggest that low numbers of CD45RO+CD45RA- Treg in FA subjects might play a role in asthma in those exposed to AAP. It is important to note that the CD45RA+CD45RO- Treg population remained similar in all groups (Figure 1D).
Figure 1. Low numbers of memory Treg in Fresno Asthmatic (FA) Cohort. Multicolor
flow cytometry performed (LSR II, BD Biosciences) on less than 500 µl whole blood
stained with antibodies and cells were gated for (A) CD45RO+ Treg in FA (n=20);
(B) CD4+CD45RO+ T cells in FA (n=20), FNA (n=20), (D) CD45RA+Treg in Treg in FA
(n=20), FNA (n=20). CBC with differential was used with % of each subset to
determine absolute.
Our data obtained from the P20 formative center between Stanford and UC Berkeley demonstrate a strong link between PAH and IgE. We also observed associations for decrements in FEV1 in relation to PAH, as well as other ambient air pollutants, NO2, NO, EC, PM2.5 and PM10 (data not shown). Associations for FEV1 were strongest with the 3 month average exposures.
The below table represents change in outcome per 1 unit increase in PAH exposure estimated in unadjusted linear models based on preliminary data from our CHAPS children.
Table 1. Total IgE is increased with increasing levels of exposure to PAH
Average PAH (ng/m3) | |||
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Outcome (N) | 1 month | 3 month | 6 month |
Total IgE | 23.34 (p<.0001) | 67.28 (p<0.0001) | 103 (p<0.0001) |
FEV1 | -0.71 (p=.08) | -1.54 (p=.01) | -1.84 (p=.07) |
Community Outreach and Translation Core
The outstanding Community Advisory Board (CAB) currently consists of 12 members, three from environmental groups, six from health groups or agencies, and three from academia (California State University-Fresno or UCSF). The non-academic affiliations are diverse, including FMM, CVAQC, Coalition for Clean Air, the Fresno County Department of Health, the Fresno-Madera Medical Society, Clinica Sierra Vista, and the American Lung Association of California. Research results were presented at four CAB meetings and CAB members provided very useful input. The CAB also has been a good venue for concerns about air quality monitoring conducted by the San Joaquin Air Pollution Control District to be communicated to Dr. Balmes, who is the physician member of the California Air Resources Board (CARB). Dr. Balmes has been able to contact appropriate CARB and Region IX U.S. EPA staff to address these concerns.
Biostatistics Core
We implemented the causal inference (semiparametric) framework that was the centerpiece of the P20. New statistical methods have been developed to provide fully adjusted (confounders) exposure-response functions for pollutants that make use of an advanced algorithm (Super Learner), which provides optimal models (variance, bias tradeoff) simultaneously from a large library of user specified algorithms. The method obviates the need from assumptions about the data generating distributions and is justified by an important theoretical result (Oracle Inequality). The Super Learner is able to show a distinct population threshold between lag 1 individual level NO2 concentrations and morning wheeze, compared to the best model included in a 5 model library. These methods allow us to produce marginal, public health relevant exposure-response function without having to pre-specify any one, single a priori model. This will provide great flexibility in our health analyses as well as improved utility for health impact assessment speciated data collected in fall/winter 2010/2011. Our Biostatistics Core has developed powerful new methods to provide population-level exposure response function curves that overcome many of the limitations of existing methods. These will allow us to provide finer scale analyses of health effects over the full range of exposures without the need to group exposures into arbitrary groups.
Exposure Core (ExC)
We have acquired and quality assured air quality data for NO, NO2, ozone, CO, PM2.5, PM10, and PM2.5 chemical constituents for 1997-2011 that are routinely collected at air monitoring stations in all 8 counties in the SJV. These data have been used to generate individual level exposure assignments for air pollutants [O3, CO, NO2, NOx, PM2.5, PM10 and PAHs] and traffic density at maternal residences to estimate trimester specific exposures of 90,000 subjects in Project 1, 5000 birth defect subjects in Project 2 and recent exposures of children in Project 3 to these air pollutants.
While PAH data are not routinely collected at these air monitoring stations, we have been collecting PAH data with speciated integrated filter samples and EcoChem PAS2000 continuous monitors in Fresno for several years, and developed temporal spatial models to estimate these exposures (Noth, 2011); PAH filter samples also were collected at 14 locations to evaluate spatial variability in Bakersfield. While subjects in projects 1 and 3 live in Fresno County, where we have extensive data on spatial variability, those in Project 2 and those expected for the expanded studies may live anywhere in the 240 mile Stockton-Bakersfield corridor. Therefore, we installed EcoChem PAS2000 monitors in five cities in the corridor, and we also collected endotoxin samples in four cities.
Future Activities:
Project 1: Effect of Multi-Level Environmental Exposure on Birth Outcomes
Our plans are to analyze the association between air pollution and birth outcomes and determine whether the associations differ by levels of neighborhood deprivation.
Project 2: Exposure to Air Pollutants and Risk of Birth Defects
Our plans and goal have essentially not changed. Many more analyses are planned in the coming year.
Project 3: Ambient Pollutants/Bioaerosol Effects on Treg Function
For this coming year, we will:
- Complete all collection of samples and clinical outcome measures every 6 months.
- Complete our analysis of repeat immune measures (i.e., Treg function, FoxP3 expression, DNA methylation of FoxP3 locus) and repeat clinical outcomes (pulmonary function tests and health questionnaires) on each subject.
- Obtain short term and long term individual estimate exposures to ambient air PAHs, PM2.5, black carbon and ozone, and then test whether there is an association of the extent of exposure in each subject with immune outcome measures in the same subject.
- If data represent interesting findings, we will submit a manuscript on the EPA-funded cohorts.
Journal Articles: 15 Displayed | Download in RIS Format
Other center views: | All 50 publications | 15 publications in selected types | All 15 journal articles |
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Balmes JR. How does diesel exhaust impact asthma? Thorax 2011;66(1):4-6. |
R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2012) |
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Gale SL, Noth EM , Mann J, Balmes J, Hammond SK, Tager IB. Polycyclic aromatic hydrocarbon exposure and wheeze in a cohort of children with asthma in Fresno, CA. Journal of Exposure Science & Environmental Epidemiology 2012;22(4):386-392. |
R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2012) |
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Hew KM, Walker AI, Kohli A, Garcia M, Syed A, McDonald-Hyman C, Noth EM, Mann JK, Pratt B, Balmes J, Hammond SK, Eisen EA, Nadeau KC. Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clinical & Experimental Allergy 2015;45(1):238-248. |
R834596 (2012) R834596 (Final) R834596C003 (Final) R834786 (Final) R835435 (2014) R835435 (2015) R835435 (2016) R835435 (Final) |
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Kohli A, Garcia MA, Miller RL, Maher C, Humblet O, Hammond SK, Nadeau K. Secondhand smoke in combination with ambient air pollution exposure is associated with increased CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clinical Epigenetics 2012;4(1):17 (16 pp.). |
R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2011) R834596C003 (2012) R834596C003 (Final) R834786 (2012) R835435 (Final) |
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Liu J, Zhang L, Winterroth LC, Garcia M, Weiman S, Wong JW, Sunwoo JB, Nadeau KC. Epigenetically mediated pathogenic effects of phenanthrene on regulatory T cells. Journal of Toxicology 2013;2013:967029. |
R834596 (2012) R834596 (Final) R834596C003 (2012) R834596C003 (Final) R834786 (2012) R835435 (Final) |
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Mann JK, Balmes JR, Bruckner TA, Mortimer KM, Margolis HG, Pratt B, Hammond SK, Lurmann FW, Tager IB. Short-term effects of air pollution on wheeze in asthmatic children in Fresno, California. Environmental Health Perspectives 2010;118(10):1497-1502. |
R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R835435 (Final) |
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Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I. Ambient air pollution impairs regulatory T-cell function in asthma. Journal of Allergy and Clinical Immunology 2010;126(4):845-852.e10. |
R834596 (2010) R834596 (2011) R834596C003 (2010) R834596C003 (2011) R834786 (2011) R835435 (Final) |
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Noth EM, Hammond SK, Biging GS, Tager IB. Mapping and modeling airborne urban phenanthrene distribution using vegetation biomonitoring. Atmospheric Environment 2013;77:518-524. |
R834596 (Final) R835435 (Final) |
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Padula AM, Mortimer K, Hubbard A, Lurmann F, Jerrett M, Tager IB. Exposure to traffic-related air pollution during pregnancy and term low birth weight: estimation of causal associations in a semiparametric model. American Journal of Epidemiology 2012;176(9):815-824. |
R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C001 (2011) R834596C001 (2012) R834596C001 (Final) |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Yang W, Lurmann F, Shaw GM. Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California. Paediatric and Perinatal Epidemiology 2013;27(4):329-339. |
R834596 (2011) R834596 (2012) R834596 (Final) R834596C002 (2011) R834596C002 (2012) R834596C002 (Final) R835435 (Final) |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Lurmann F, Shaw GM. The association of ambient air pollution and traffic exposures with selected congenital anomalies in the San Joaquin Valley of California. American Journal of Epidemiology 2013;177(10):1074-1085. |
R834596 (2011) R834596 (2012) R834596 (Final) R834596C002 (2011) R834596C002 (2012) R834596C002 (Final) R835435 (Final) |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Yang W, Lurmann FW, Shaw GM. Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth Defects Research, Part A: Clinical and Molecular Teratology 2013;97(11):730-735. |
R834596 (2012) R834596 (Final) R834596C002 (2012) R834596C002 (Final) R835435 (Final) |
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Padula AM, Mortimer KM, Tager IB, Hammond SK, Lurmann FW, Yang W, Stevenson DK, Shaw GM. Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California. Annals of Epidemiology 2014;24(12):888-895e4. |
R834596 (2012) R834596 (Final) R834596C001 (2012) R834596C001 (Final) R835435 (2015) R835435 (2016) R835435 (2018) R835435 (Final) |
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Padula AM, Balmes JR, Eisen EA, Mann J, Noth EM, Lurmann FW, Pratt B, Tager IB, Nadeau K, Hammond SK. Ambient polycyclic aromatic hydrocarbons and pulmonary function in children. Journal of Exposure Science & Environmental Epidemiology 2015;25(3):295-302. |
R834596 (2012) R834596 (Final) R835435 (2014) R835435 (2015) R835435 (2016) R835435 (Final) |
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Yang W, Carmichael SL, Roberts EM, Kegley SE, Padula AM, English PB, Shaw GM. Residential agricultural pesticide exposures and risk of neural tube defects and orofacial clefts among offspring in the San Joaquin Valley of California. American Journal of Epidemiology 2014;179(6):740-748. |
R834596 (Final) R834596C002 (Final) |
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Supplemental Keywords:
birth outcomes, premature birth, disparities, air pollution, traffic, congenital abnormalities, pregnancy, air pollution, traffic, biology, genetics, epidemiology, analytical, California, CA, Region 9, transportation, air pollution, allergic, asthma, childhood asthma, environmental health, epidemiologic studies, health, human, immune system, immune tolerance, immunopathology, inflammation, lung, pollutant, regulatory T-lymphocyte;Relevant Websites:
Children's Health & Air Pollution Study - San Joaquin Valley Exit
Stanford Medicine | Sean N. Parker Center for Allergy and Asthma Research Exit
Resources | Children's Health & Air Pollution Study - San Joaquin Valley Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834596C001 Effect of Multi-Level Environmental Exposure on Birth Outcomes
R834596C002 Exposure to Air Pollutants and Risk of Birth Defects
R834596C003 Ambient Pollutant/Bioaerosol Effects on Treg Function
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.